Sulfathiazole preparation



Patented Apr. 15, 1952 SULFATHIAZOLE PREPARATION Thomas F. Cleary, (In,New Brunswick, N. J., as-

signor to E. R. Squibb & Sons, New York, N. Y., a corporation of NewYork No Drawing. Application June 29, 1946,

Serial No. 680,513

2 Claims. (01. 260-239.95)

This invention relates to the production of sulfathiazole.

Prior to this invention, sulfathiazole was generally prepared bycondensing one mol of p-acetamino-benzenesulfonyl chloride with one molof 2-amino-thiazole in the presence of pyridine, and deacetylating theresulting N -acetylsulfathiazole, a high degree of dryness beingessential for the condensation.

Also, prior to this invention, sulfathiazole had been prepared bycondensing two mols of p-acetamino-benzenesulfonyl chloride with one molof 2-amino-thiazole to produce a bis compound-i. e., thedi-(acetamino-benzenesulfonyl) derivative of 2-amino-thiazole, orbis-N-(pacetamino-benzenesulfonyl) -2-amino-thiazole and hydrolyzing itto sulfathiazole (cf. application Serial No. 334,990, filed May 13,1940, which was vested in the Alien Property Custodian and publishedApril 20, 1943 and is now abandoned). Although such process employs anadditional mol of p-acetamino-benzenesulfonyl chloride, thatdisadvantage is partially offset when the reactants are employed in thewet state (dryness not being essential for the condensation).

Such wet process, however, gives relatively low yields of the biscompound (and consecpientlyv low overall yields of sulfathiazole).

-It is the object of this invention to provide:

[A] an advantageous method of preparing sulfa-- thiazole; [B] animproved method of preparing di p R, benzenesulfonyl) amino-thiazole, Rrepresenting a substituent capable of conversion into an amino group 35derivative of Z-amino-thiazole; and [C] an ad especially thedi-(p-acetamino-benzenesulfonyl) vantageous method of convertingdi-(p-R- benzenesulfonyl) derivatives of thiazoleespecially the,di(p-acetamino-benzenesulfonyl) derivative of 2-amino-thiazoleintosulfathiazole.

In the practice of this invention, a di-(p-R- benzenesulfonyl)derivative of 2-amino-thiazole is prepared by reacting thep-R-benzenesulfonyl halide with 2eamino-thiazole in the presence of anacid-binding agent, in a two-phase medium of water and an inert organicsolvent for the reactants, inter alia, ether, ethylene dichloride,pyridine, acetone, and mixtures thereof. Preferably, the inert organicsolvent is acetone; the two-phase acetone-water medium being formed bysubstantially saturating the water with salt (sodium chloride).

The utilizable acid-binding agents (or acid-v derivatives of 2- 2 amino2 V. nate (which is preferred), ammonium hydroxide,v sodium carbonate,pyridine, dimethyl-aniline, and (under proper conditions) sodiumhydroxide and magnesium hydroxide. V c

Other salting-out salts may be used in place of sodium chloride toproduce a two-phase medium, inter. alia, ammonium sulfate, sodiumsulfate, and other alkali (including alkalineearth-metal and ammonium)halides.

Desirably, the amount, of sulfonhalide'fi. e.

p-R-benzenesulionyl halide) used is in slight.

excess over the ratio of 2 mols of the sulfon-v halide to 1 mol ofZ-amino-thiazole; the amount of water used is the minimum required toobtain,

workable fluidity in the reaction mixture; the amount of salting-outsaltused is substantially that required to saturate the amount of waterused; and the amount of acid-binding agent used is that theoreticallyrequired, i. e., 1 mol per mol' of the sulfonhalide.

The di-(p-R-benzenesulfonyl) derivative of 2- amino-thiazole obtainedmay then be subjected to (alkaline or acid) hydrolysis to split'ofl oneof the p-R-benzenesulfonyl groups and obtain the desired 2-(p-R-benzenesulfonamido) -,thi-,

azole. Where R is an acylamino group, mild alkaline hydrolysis isadvantageous (over the:

more direct acid hydrolysis), because it permits easy recovery of partof the additional sulfonhalide used, in the form of an acyl-sulfanilicacid.

Preferably, the di-:(p-R-benzenesulfonyl) ce-f rivative of2-amino-thiazole obtained (as well as. of such-compounds obtained byother methods) is reacted with a member of the group con-' sisting ofammonia and basic organic amines which can be condensed withp-R-benzene-n sulfonyl halides to provide, chemotherapeutic agents,another (or more of the same) 'p-R-z benzenesulfonamide being therebyformed concurrently with the 2-(p-R-benzenesulfonamido) thiazole; andwhere diiierent, these sulfonamides may, be separately recovered.

Among the basic organic amines utilizable in, the practice of thisinvention areguanidine and the di-(p R 1- benzenesulfonyl) derivative ofz-amino-thiazole" homosulfanilamide. Desirably,

is hydrolyzed with an aqueous solution of a member of the groupconsisting of ammonia and guanidine, to obtain p-R-benzenesulfonamide.and N-(p-R-benzenesulfonyl) -guanidine, respectively, concurrently withthe readily separable 2- (p-R-benzenesulfonamido) -thiazole;

Among the substituents capable of conversion 1 into an amino group(represented by; R). are;

acylamino, nitro, azo, and halo; such substituent (in the final reactionproduct) being converted into an amino group in the conventional manner.Thus, where R in the reactant p-R-benzenesulfonyl halide is an acylaminogroup, the acyl reaction product obtained is deacylated (or hydrolyzed)in the conventional manner (e. e., by heating with sodium hydroxidesolution); and when R in the reactant is nitro (i. e., the reactant is ap-nitro-benzenesulfonyl halide), the nitro reaction product obtained isconverted into the corresponding amino compound in the usual manner (e.g., by reduction with iron and hydrochloric acid, or by hydrogenation inthe presence of a palladium catalyst).

The process of this invention is especially applicable to the productionof sulfathiazole along with sulfanilamide or sulfaguanidine from I adi-(p-acylamino-benzenesulfonyl) derivative of 2-amino-thiazole. In suchprocess, the sultan-- amides formed may be separately recovered bycooling the reaction mixture, separating the precipitated N-acyl-sulfanilamide or N -acyl-sulfaguanidine, acidifying the filtrate,"and recovering the precipitated N -acyl-sulfathiazole.

In the preparation of bis" compounds in accordance with this invention,the reactants may be mixed in any order. Thus, all the reactants exceptthe acid-binding agent may be mixed together first, and the acid-bindingagent then added; or, preferably, all the reactants except thesulfonchloride are mixed together, and the sulfonchloride is then addedas a wet cake or slurry.

The ammonia employed for the hydrolysis of EXAMPLE 1 (a) A solution of50 g. 2-amino-thiazole in 200 ml. (160 g.) acetone is added to asolution of 120 g. sodium chloride and 90 g. sodium bicarbonate in 400ml. water; the temperature of the mixture is adjusted to -30 0.; and 240g. p-acetamino-benzenesulfonyl chloride is added to the mixture withgood agitation as rapidly as foaming will permit, and stirring iscontinued until the evolution of CO2 has ceased and a smooth slurry (ofthe "bis compound) is obtained.

i (b) To this slurry is added 110 g. ammonia water (26-28% and themixture is agitated and maintained at 65 C. for 2.5 hours. The reactionmixture '(a thin, amber-colored slurry of sandy crystals) is cooled to20 0., and filtered. The

separated crystals (of N -acetyl-sulfanilamide) Darco (anactivatedcharcoal) for one hour, and i 4 then filtered; and the pH of thefiltrate is adjusted to 5.5 by addition of 38% hydrochloric acid (about90 g. being required). The resulting precipitate (of N-acetyl-su1fathiazole) is filtered oiT, and washed with two 100 ml.portions of water. The dry, light-yellow product melts at 250-254 C. andweighs 140-135 g., representing 88-91% of the theoretical yield based onthe 2- amino-thiazole used.

(c) 130 g. of the N -acetyl-sulfathiazole obtained is dissolved in asolution of 40 g. sodium hydroxide flakes in 200 ml. water, and theresulting clear, light-red solution is maintained at 65 C. for about 2hours. [It is necessary to determine with certainty that thedeacetylation is complete-in order to avoid contamination of thesodium-sulfathiazole with N -acetyl-sulfathiazole; and the solutionshould therefore be maintained at 65 C. until no acid-insoluble matterremains, asdetermined by the addition of a small sample of the reactionmixture to an excess of strong hydrochloric acid.] When thedeacetylation is complete, a solution of 50 g. sodium hydroxide flakesin ml. water is added, and the mixture is allowed to cool several hoursto 20 C. The sodium-sulfathiazole crystals formed are filtered off,washed free of dark mother liquor with two 50 ml. portions of 15% sodiumchloride solution (the amount of sulfathiazole remaining in the motherliquor is negligible), and (if desired) converted into sulfathiazole inthe usual manner (yield 89-91 g., representing -82% of the theoreticalbased on th N -acetyl-sulfathiazole used).

' (d) 102 g. of the N acetyl-sulfanilamide obtained is added to amixture of 50 g. 34% hydrochloric acid and 300 ml. water, and the mixture is heated to boiling for 20 minutes, then treated with 2 g. Darcofor 20 minutes, and filtered. The filtrate is neutralized to pl-I withabout 60 g. 32% sodium hydroxide solution, and cooled to 20 C.; and theresulting crude sulfanilamide crystals are filtered off, and washed withtwo 50 ml. portions of cold water. The product melts at 163-164 C. andweighs 7'7 g. (representing of the theoretical yield based on the N-acetyl-sulfanilamide used). The crude sulfanilamide is further purifiedby dissolving it in 1 liter of water by heating to 95 C., treating thesolution with 1 g. Darco, filtering, cooling the filtrate to 15 C.,filtering ofi the resulting sulfanilamide precipitate, washing it withtwo 50 ml. portions of cold distilled water, and drying. Thesulfanilamide thus obtained melts at 164466 C. and weighs '70 g.(representing 755% of the theoretical yield from one-half of thesulfonchloride used).

EXAMPLE 2 (a) Materials 2-amino-thiazole (dried)-35 lbs, assaying 94.4%

Pro cedwve All materials except the sulfonchloride are mixed together ina 75-gallon glass-lined reactor equipped with an 801?...1. M-anchor-type. agitator. the sulfonchloride is added over a period of onehour (while agitating), the rate of addition being governed by thefoaming of the batch, and the reaction mixture is agitated for two hoursafter evolution of carbon dioxide has ceased. The resulting smoothslurry is centrifuged, and the separated bis compound is dried. It islight brown in color, melts at 123-125 C., and weighs 160 lbs.(representing 97.5% of the theoretical yield). [The bis compound may bepurified by dissolving in 6 parts warm acetone, adding an equal volumeof water, and chilling, being thereby obtained as fine white needlesmelting with decomposition at 129l30 0.]

(2)) Materials Pounds Bis" compound (dry) 160 Water 400 38% hydrochloricacid 100 34% sodium hydroxide solution 175 Darco Procedure The bis"compound, water, and hydrochloric acid are charged into a 75-gallonglass-lined reactor, and the mixture is heated with agitation to 98 C.(careful maintenance of the temperature below the boiling point beingrequired to prevent serious foaming). After about 50 minutes, thereaction mixture becomes clear (indicating completion of thedeacetylation); the Darco is then added, and the mixture is cooled to 50C. and I'lltered through a rubber-covered filter press. [If

considerable sulfathiazole hydrochloride has crys-.

tallized from the solution, it is necessary to reslurry the press cakein water to recover it, or filter at a higher temperature.] The filtrate(and Washes) are adjusted to pH 6.5 by addition of the sodium hydroxidesolution, and the crude sulfathiazole precipitated is separated anddried. The product weighs 65 lbs. and assays 97.0% sulfathiazole(representing 76.2% of the theoretical yield based on the2-aminothiazole) (b. alternative.) The unisolated bis compound, i. e.,the slurry obtained as described in section a, is converted intosulfathiazole (and sulfanilamide) by the procedure described in sectionsb and c of Example 1.

EXAMPLE 3 (a) Materials Z-amino-thiazole (wet)-32 lbs., assaying 94.4%(0.252 mol) p-Acetamino-benzenesulfonyl chloride126 lbs.,

assaying 95.5% (0.51 mol) Acetone-80 lbs. Sodium chloride70 lbs. Sodiumbicarbonate-45 lbs. (0.53 mol) Water-200 lbs.

Procedure Same as in section a of Example 2, except that first the2-amino-thiazole is dissolved in the acetone, and the solution istreated with 1 lb. Darco and filtered before charging into the reactor(this treatment removing insoluble matter and colored impurities fromthe 2-amino-thiazole). The bis compound, separated by centrifuging,washed with water, and dried, is Very 6 light tan in color, melts at 130C., and weighs 124 lbs. (representing 99.0% of the theoretical yield).

(2)) Materials Procedure The water and hydrochloric acid are mixed andheated to 98 C., the bis compound is added over a. period of 30 minutes,and the temperature is then maintained at 100-103 C. for 40 minutes. TheDarco is then added, and the batch is cooled to 55 C. and filteredthrough a rubber-covered filter press. The filtrate is cooled to 25 C.,and the pH adjusted to 6.5 by addition of the sodium hydroxide solution;and the precipitated crude sulfathiazole is separated and dried. Theproduct is light tan in color, melts at 187-190 C., and weighs 50.5 lbs.

On conversion of this crude sulfathiazole into sodiumsulfathiazole andreconversion to sulfathiazole as described in section 0 of Example puresulfathiazole is obtained in a yield of 68% of the theoretical (based onthe 2-amino-thiazole).

(b, alternative.) The bis compound formed in section a, beforeisolation, is converted into sulfathiazole (and sulfanilamide) by theprocedure described in sections "b and c of Example 1.

EXAMPLE 4 is heated at 40 C. for 2 hours. The mixture is' then cooled to0 C., and the precipitate (acetylsulfanilic acid) is separated; and themother liquor is neutralized, and the resulting precipitate (N-acetyl-sulfathiazole) is separated, and deacetylated in the usualmanner (e. g., by heating with aqueous sodium hydroxide solution).

EXAMPLE 5 (a) 65 g. anhydrous magnesium sulfate is dissolved in 150 ml.water, and a solution of 40 g. sodium hydroxide in 100 ml. Water isadded thereto. The resulting heavy slurry (of magnesium hydroxide) isadded to a solution of g. sodium chloride in 400 ml. water; a solutionof 50 g. 2- amino-thiazole in 200 ml. acetone is added; and, whileagitating vigorously, 282 g. wet p-acetamino-benzenesulfonyl chloride(containing 240 g. of the dry sulfonchloride) is added rapidly. Thetemperature rises to 40 C., and the pH remains constant at about 8.0.Agitation is continued for 2 hours, and the insoluble reaction product("bis compound) is filtered off and washed with 1 liter water.

sulfanilamide and N -acetyl-sulfathiazole formed.

EXAMPLE 6 (a) A solution of 120 g. sodium chloride in 400 ml. water is.mixed with a solution. of 50 g. 2

iterates and, while agitating vigorously, a solution of 40 g." sodiumhydroxide in 160 ml. water is added '.at"such rate as tomaintain thepi-I of the reacti'on mixture at 8.0. The reaction is complete irr3hours.

(b) The reaction mixture (a slurry of the his compound) is mixed with150. ml. ammonia'water, and the mixture is heated at 65 C. for 2 hours;and the reaction mixture is then treated as 'des'crib'edin section bj'of'Example 1, to isolate "the N -acetyksulfaniiamide and N '-acetyl-sul-"iathiazole formed.

EXAMPLE} 7 Materials 'D'i ip acetamino benzenesuifonyi) A derivative of"added in portions, while'agitating the mixture and maintainingits'temperature at 68-77" F. The mixture is agitated for 15 minuteslonger, and cooled to 32 F.; and, while agitating, the ffbisf compoundis then added at such rate that the temperature ismaintained at 32-40"and the agitation and temperature maintenance continned for 15 minutesbeyond the addition. After the reaction mixture has stood at roomtemperature ior z hours. 100 gals. wateris added, while agitating; andafter several hours, the alkaliinsoluble, material (N -acetylsulfaguanidine) is filtered off. i

Thefilter cake is washed with water (the wash being; combined ,with thefiltrate), and dried, yielding/a crude N -acetyl-sulfaguanidine meltinga t 255'260 C. The N -acetyl-sulfaguanidine is then de-acetylated in theconventional manner, e. g., by the procedure'des'cribed for thedeacetylation of N acetyl sulfanilamidein section d'fbf'ExampleL.

The combined alkaline filtrate and .wash of thefilter' cake is adjustedto pH '4 by'addition of concentrated hydrochloric acid, while agitating;and; after the'reaction mixture has stoodfor 12-16; hours, "thesupernate is removedjand the precipitate is recovered by filtration,washed, and "dried. The crude N' acetyl sulfathiazole thus obtainedmelts at255$257 C. It isdea'ctylatedjin-the'conventional manner,"e.'-g.,as described in section of Example 1.

Materials Di ip-acetamino-benzenesulfonyl) derivative of "g-amindthiazole (e.g the crude bisf com- {pound obtained as described insection a of Example 22-1-49}! g. Py ine- 010 ec- 2-arnino-thiazole-'10.1 g.

'Procecllure jZ- aniingS-thiaZole,11s [dissolved in the pyridine; -and,*at room temperature, the bis (smatteis added to thesolutionf in s ir iit rtions, while" agitating. The temperature'tbf the reaction mixture(which has risen "to '35'.C.) is

then raised to -75? C. and maintainedthei e roi- 2' hours by heating thereaction mixture one.

steam bath. iThe' reaction mixturelis thenfco'oled to room temperature;and the insoluble material therein is removed by filtration; and thefilter cake is washed. 'ihe firstcrop of N -acetyl-suliathiazole thusobtained weighs 27 giand melts" .at 256-25? C. The filtrateimoth'er'liquor) is' then concentrated under reduced pressure, yieldingl'a secondcrop weighing 13.5 g. ,and mel'tingat 252-255 C. The combined crude N-acetylsulfathiazole is dissolved, in dilute sodium hydroxide solution,treated with Darco, and filtered; and the filtrate is acidified withhydrochloric acid. The resulting precipitate. is filtered off, washed,anddried,'yielding 38.5 g. of a purified N -acetylsulfathiazolemelting'at 258 260? C.

The N -acetyl sulfathiazole' is deacetylatedfin the conventionalmanner,e. g., as des'cribed'i'n section 0 of Example 1. [The 'umeacted 2arninothiazole can be recovered and reused] The invention may bevariously otherwise embodiedwithin the scope of the appended claims.

,I claim: Y I

1. In the method of preparing sulfathiazole, the step of reacting twomols of a p R-sbenzenesulfonyl halide, R representing asubstituentlcapable of conversion into an amino group and selected fromthe class consisting .of. acy1amino,.nitr.o,. azo and halo, with one molof 2-amino-thiazole in the presence of anuacid-binding, agent, in a.inediiun essentially comprising acetone and a substantially-saturatedaqueous solution of an alkali halide, while maintaining the phases ofthe medium in intimate contact with eachpthert 2. Inthemethod ofpreparing suliathiazole, the step of reacting, two. mols ofpeacetamino-benzenesulfonyl chloride with one inol of 2-aminothiazole inthepresence of sodium bicarbonate, in a ed m e e ti ly qmnri i e ace o ean a substantially-saturated aqueous solution. of Sodium i iwhi e .maitaimne the. pha e of the medium in intimate contact with each other.

"tseinsajaaisea.

Entertainers s crrnn The following references are of record in the fileof this patent' UNITED srn'rns time 4th ed., vol. I, (Longmans,,N.Y.,1937) p.66

Raiziss et. al.: J. Amer. Chem. 8001, Vol.63, pp. 3124-3126, r1941). 7 c

SerQNo.334,990 Foldi'et a1. (AQP. C.), pub lishd April 20, "1943.

1. IN THE METHOD OF PREPARING SULFATHIAZOLE, THE STEP OF REACTING TWOMOLS OF A P-R-BENZENESULFONYL HALIDE, R REPRESENTING A SUBSTITUENTCAPABLE OF CONVERSION INTO AN AMINO GROUP AND SELECTED FROM THE CLASSCONSISTING OF ACYLAMINO, NITRO, AZO AND HALO, WITH ONE MOL OF2-AMINO-THIAZOLE IN THE PRESENCE OF AN ACID-BINDING AGENT, IN A MEDIUM,ESSENTIALLY COMPRISING ACETONE AND A SUBSTANTIALLY-SATURATED AQUEOUSSOLUTION OF AN ALKALI HALIDE, WHILE MAINTAINING THE PHASES OF THE MEDIUMIN IMTIMATE CONTACT WITH EACH OTHER.